The predominant mechanism in most cases of traumatic brain injury (TBI) is diffuse axonal injury (Whyte and Rosenthal, 1993). While axonal injury is common in all TBI regardless of severity (Povlishock et al., 1992; Mittl, 1994), a shearing of the axons occurs in human diffuse axonal injury (DAI) leading to progressive changes that ultimately may result in the loss of connections between nerve cells. The slow progression of events in DAI continues for up to several weeks after injury creating a window of opportunity for therapeutic intervention.
There are approximately 500,000 new cases of TBI in the U.S. each year (Frankowski, 1985), and the incidence requiring hospitalization is estimated to be approximately 200-225/100,000 population (Frankowski, 1986; Cams, 1993). Currently, it is estimated that brain injuries account for 12% of all hospital admissions in the United States (Sandel, 1993). When compared to spinal cord injury, which accounts for less than 1% of hospital admissions, it is clear that TBI is a medical care problem which has a significant impact financially within the United States. Approximately 30,000-44,000 people will survive a severe TBI with GCS score<9 (Glasgow Coma Score Scale, Jennett, 1981) in the U.S. each year and more than 70,000 will be significantly disabled from moderate to severe TBI (GCS#10) (Whyte & Rosenthal, 1988). Yet with new medical management techniques, less than 10% will remain in a persistent vegetative state (Whyte, 1993; Rosner, 1992; Rosner, 1990). A GCS score of eight or less generally reflects a state of unconsciousness in which the patient demonstrates no eye opening, does not follow simple commands to move muscles, and has vocalizations which are limited to sounds. Such signs are indicative of severe brain injury (Whyte, 1993; Jennett, 1975, Jennett, 1981).
Approximately 52,000 to 56,000 people die each year from TBI (Kraus et al., 1996), resulting in direct costs approximated at more than $50 billion annually (Max et al., 1991). The costs of severe TBI to the individual and family are extremely high (McMordie, 1988). Acute medical and rehabilitation bills are often around $100,000 with some considerably higher (McMordie, 1988). The Model Systems Database for Traumatic Brain Injury demonstrates there is a correlation between the average Disability Rating Score and the combined acute care and rehabilitation charges (Bullock et al., 1995). Those with a severe TBI (GCS score of 6-8) have average combined charges of $110,842, and those with a very severe TBI (GCS score 3-5) have average combined charges of $154,256 (Lehmkuhl, 1993). About one-half of all TBIs are transportation related (Whyte, 1993; Lehmkuhl, 1993) and these patients have some of the highest combined charges for acute care and rehabilitations (Lehmkuhl, 1993). This may be related to the mechanism of TBI in high speed motor vehicle crashes, specifically the presence of diffuse axonal injury (DAI) being most prevalent in the midbrain and brain stem areas (Whyte, 1993). Clearly, brain injuries of this severity that occur with high speed acceleration-deceleration injuries, have the highest costs to society. TBI clearly causes more mortality, morbidity and probably more economic loss than HIV infection in the United States.
Motor vehicle crashes of all types are responsible for approximately 40%-50% of the TBI admissions recorded in the Model TBI Systems Database (Lehmkuhl, 1993). The predominant mechanism of injury is considered to be diffuse axonal injury (DAI). Approximately 30%-40% of the fatal head injuries involve diffuse axonal injury by pathological examination (Bennett et al., 1995; McLellan, 1990). However, based on beta-amyloid precursor protein immunostaining, axonal injury may be present in all cases of fatal head injury (Gentleman et al., 1995). In cases of persistent vegetative states, Kampfl et al. (1998) recently found that all cases had evidence of DAI in magnetic resonance imaging (MRI). Diffuse axonal injury occurs even in the absence of a blow to the head and is more prevalent than previously realized. Even in mild head injury, diffuse axonal injury is present in almost ⅓ of the cases (Mittl et al., 1994). The defining characteristic of DAI is the morphologic change to the axons which occurs over the course of several days to weeks and the fact that multiple regions of the brain are injured. While a component of DAI is present in blunt or penetrating trauma injury, it is at the periphery of the injury zone and is much less significant than the predominant mechanism of injury. DAI is the major mechanism of injury in high speed acceleration-deceleration injuries associated with motor vehicle crashes. While all four mechanisms of TBI (DAI, blunt trauma, penetrating trauma, axonia) may be involved in such an injury, it is the predominant mechanism of injury under this condition.
For human head injuries resulting from car collisions, the average velocity for the onset of severe injuries is 6.7 m/s (or 24.1 km/hour) as mentioned by Lorenzo et al. (1996). Most studies have been directed to the analysis of impact to the head. The Head Injury Criterion (HIC) is one method that is commonly used to assess the severity of an impact (Chou and Nyquist, 1974). Although it is considered to be the best available head injury indicator, a new finite element model using a dummy head has taken into account the effects of rotational and translational acceleration (Ueno and Melvin, 1995). Using this model, the dominant effect of translational acceleration was on principal stresses and rotational acceleration was on shear stresses.
Current research appears to point of plastic deformation within and of the axons that leads to the predominant cause of injury. The elastic tissues of the brain have plastic properties. Once the level of force is applied to a plastic substance, it is the time period over which it is applied that causes the amount of deformation. If the elastic memory of the substance is exceeded then there will be shearing and tearing. The high speed motor vehicle accident with deceleration lasting more than one to three seconds or several seconds of repetitive shaking can produce enough force for this to happen.
Materials research indicates that there is an amount of force which must be delivered below which plastic deformation of substances does not occur. In fact, the Gadd severity index initially attempted to measure the severity of injury utilizing an acceleration/time curve (Gadd, 1998). This critical amount of force appears to be essential in the development of injury (McLean & Anderson, 1997). This is very different from the contusive model of TBI where the forces are applied over milliseconds.
This indicates that once the amount of force has reached a threshold, it is the length of time the force is applied with the associated plastic deformation that is the predominant factor which causes the intracellular damage to the organelles within the axon. Hence, there is a continuum over which DAI occurs in TBI. After the threshold of necessary force to create plastic deformation is reached, it may be the length of time over which it is applied that determines the amount of DAI. This would explain the findings of Foda et al. (1994) where some DAI was noted in areas adjacent to a contusion injury in rats. Unfortunately, most TBI occurs over several seconds (high speed transportation crashes) where DAI is likely to be the predominant method of injury. This is supported by the fact that many severe TBI patients have minimal changes noted on CT scan following motor vehicle crashes.
Motor vehicle crashes are the predominant cause of DAI. A component of DAI is felt to be present in all motor vehicle crashes where the patient has lost consciousness (Whyte, 1988). For many years, DAI has been known to be associated with a coma of immediate onset after brain injury, but the diagnosis could only be established by autopsy. Indeed, the clinical syndrome of coma without any preceding lucid interval, decerebration, and autonomic dysfunction were often ascribed to primary brainstem injury. However, it is now clear that primary brainstem lesions do not occur in isolation but rather in association with DAI and usually involve the cerebral hemispheres and cerebellum in addition to the brainstem (McLellan, 1990). Evidence of the mechanism of injury can be elicited by pathological studies of patients killed from high speed transportation injuries (Pounder, 1997) as well as pathological studies of “shaken baby syndrome,” a distinct subset of DAI (Nelson et al. 1993). A recent case report (Pounder, 1997) indicates that this shaking mechanism of DAI injury also applies to adults. The injury is characterized by specific neuropathological findings. On CT and MRI, this usually involves hemorrhagic punctate lesion of the corpus callosum, pontine-mesencephalic junction adjacent to the superior cerebellar peduncles and diffuse axonal damage in the white matter of the brain, brainstem and cerebellum which begin to atrophy within two weeks after injury (Whyte, 1988; Blumbergs, 1994).
Diffuse axonal injury in humans is characterized by widespread damage to axons in the cerebral hemispheres, the cerebellum and the brain stem and is a consistent feature of TBI (Adams, 1977; Adams, 1989; McLellan, 1990). The histological features of DAI depend on the length of time after injury, but within a day or so after injury there is evidence of damage to axons in the form of axonal bulbs. The initial findings are usually characterized microscopically utilizing neurofibrillar stains and stains for microglia which are abundant in the degenerating white matter. These findings are produced by the shear or flow of cytoplasm from the proximal end of a severed axon. Subsequently, the microscopic features correspond to Wallerian-type axonal degeneration as the axon disintegrates, which is probably due to metabolic disruption from injury and damage to the internal organelles from the lack of membrane integrity. In the first two years there is active myelin degeneration and in patients surviving longer, demyelination is the final stage of the process (McLellan, 1990). The result of the traumatic injury to the axons leads to the disconnection with various target sites, which is assumed to translate into the morbidity seen (Gennarelli, 1982; Povlishock, 1992). The severity of injury based on the histopathological changes has been graded in humans but not in experimental animals (Adams, 1977; Adam, 1989). The Adams classification (Adams, 1977; Adams, 1989) is used in human autopsy material, to classify the degree of DAI as mild, moderate or severe. In this classification, mild (grade 1) is characterized by microscopic changes in the white matter of the cerebral cortex, corpus callosum, and brain stem and occasionally in the cerebellum. Moderate (grade 2) is defined based on focal lesions in the corpus callosum. In severe (grade 3), there are additional focal lesions in the dorsolateral quadrants of the rostral brain stem (commonly in the superior cerebellar peduncle). This scheme has not been used for non-primate models because different regions of the brain are injured in the present models. However, it may be possible to apply this scheme to an appropriate model of DAI in small animals that is currently under development.
When a spinal cord injury or traumatic brain injury occurs, a cascade of damaging events begins which greatly increases the injury to the central nervous system (CNS). One basic factor that has been identified at the center of these events is calcium (Ca++) ions.
Up to now, drugs have been used that are only marginally effective in preventing this cascade of events and non-steroidal inflammatory drugs (NSAIDS) have not been useful in animal models for neurotrauma. In part, this may be attributed to the fact that most NSAIDS also inhibit platelet function and consequently may increase bleeding. Furthermore, certain NSAIDS don't cross the blood brain barrier.
Recently there have been a few articles on the use of intrathecal NSAIDS for pain (Pain 1998, Southall et al.; J. Pharmacol. and Exp. Ther. 1997; 281:1381-91). Also, U.S. Pat. No. 5,914,129 to Mauskop discloses the use of magnesium containing analgesics for alleviation of pain such as from migraine headaches. Of these drugs aspirin, indomethacin, lysine clonixinate, and ketoprofen have been utilized. There have been no reports of intrathecal use in neurotrauma, for imparting neuroprotective effects, nor for the reduction or prevention of neuronal injury from inflammatory conditions. However, aspirin, which was probably the most potent and/or efficacious agent, could still inhibit platelets significantly. Aspirin crosses out of the CSF generally through the choroid plexus to the systemic circulation rather than the neural tissue. Even a baby aspirin a day is a potent inhibitor of platelets. Indeed, aspirin carries a considerable increased risk for intracerebral hemorrhage (Reymond et al. Neurosurgery Reviews 1992; 15:21-5). The inflammatory cascade that can be affected by NSAIDS include a reduction of arachidonic acid which initiates a metabolic cascade that produces inflammatory eicosanoids that promote neutrophil invasion and production of strong oxidants (Juurlink et al. J. Spinal Cord Medicine 1998; 21:309-34). This is most often by inflammatory leukotrienes. Even in the absence of enzyme activation arachidonic acid by the development of isoleukotrienes which are biologically active free radicals. Finally, NSAIDS reduce the production of inflammatory cytokines produced following CNS trauma which play a role in the development of secondary mechanisms of damage. NSAIDS reduce bradykinins and may reduce the production of platelet activating factor mediated induction of thromboxane A2. These substances administered early on with cytokines and platelet activating factors may induce late regeneration of the axons and neurons, but it is clear they cause damage soon after injury.
In addition to the use of NSAIDs for treatment of neurotrauma, a new drug developed from the venom of a mollusk (conotoxin) that forms the conoshell has the potential to stop cascade initiated following traumatic brain injury or neurotrauma because it is directed at multiple calcium channels (pathways).
Limited success has been reported with drugs directed towards blocking the calcium channels but with untoward side effects. Furthermore, there appear to be many types of calcium channels that have been identified including L, N, P, Q, and T. Only L-type channel blockers have been marketed to reduce cerebral injury and these have had limited utility in only aiding in those with spontaneous intracerebral hemorrhage. However, there has been particular interest in blocking N-type channels.
Systemic delivery, via the blood stream, for example, of Ca-channel blockers has also been associated with problems in dropping the mean arterial pressure in trauma to the CNS. This results in a drop in the cerebral perfusion pressure. The cerebral perfusion pressure, defined as to the mean arterial blood pressure minus the intracranial pressure, is the physiologic variable that defines the pressure gradient driving cerebral blood flow and metabolite delivery, and is, therefore, closely related to central nervous system ischemia, the final point in the biochemical pathway that may double the amount of central nervous system injury from the initial injury.
The use of conotoxins for the treatment of neuronal damage related to an ischemic condition affecting the central nervous system is disclosed in U.S. Pat. No. 5,189,020 to Miljanich et al. ('020) issued Feb. 23, 1993. Miljanich et al. '020 disclosed the use of conotoxins in a method of treatment for reducing neuronal damage related to an ischemic condition in a human patient by administering a pharmacologically effective amount of a synthetic conotoxin to the patient. The method discloses the administration of the synthetic conotoxin via intracerebroventricular administration. However, it is well known that ischemic neural injury is very different from diffuse axonal injury or even direct trauma to the neurons with cell membrane disruption. Ischemic neural injury appears to involve different cellular mechanisms of injury. Additionally, Miljanich et al. disclose only L-type calcium channel blockers which have only been clearly successful in those conditions where there has been subarachnoid hemorrhage (Neurology 1998; 50:876-83) but not in traumatic brain injury without subarachnoid hemorrhage (J. Neurosurgery 1994; 80:797-804), or ischemic stroke (Stroke 1992; 23:3-8). Additionally, Miljanich et al. suggests that calcium channel blockers affect outcome by vasodilating the blood vessels; however, Applicants have discovered that the calcium channel blockers act directly on neurons as well.
Accordingly, it would be advantageous and desirable to have a method of treating the injuries associated with both traumatic brain injury and spinal cord injury (neurotrauma) by the intrathecal and/or intraventricular administration of non-steroidal anti-inflammatory drugs and/or by administering a natural omega conotoxin which interrupts the influx of extracellular calcium thereby both methods preventing or lessening the severity of CNS injury and which also overcomes the drawbacks and disadvantages of the prior art described above.